This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, D. Articles by Giguère, V. Search for Related Content PubMed PubMed Citation Articles by Lu, D. Articles by Giguère, V.

Requirement of Ras-Dependent Pathways for Activation of the Transforming Growth Factor ß3 Promoter by Estradiol¹

Molecular Oncology Group (D.L., V.G.), McGill University Health Center, Montréal, Québec, Canada H3A 1A1; and Departments of Biochemistry, Medicine and Oncology (V.G.), McGill University, Montréal, Québec, H3G 1Y6 Canada

Address all correspondence and requests for reprints to: Dr. Vincent Giguère, Molecular Oncology Group, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: vgiguere{at}dir.molonc.mcgill.ca

It has been previously observed that the transforming growth factor ß3 (TGFß3) gene can be activated by both estradiol (E₂) and selective estrogen receptor modulators (SERMs) in vivo but that only SERMs have a potent stimulatory effect on the TGFß3 promoter in cultured cells. We demonstrate in this report that E₂ can act also as a potent inducer of the TGFß3 promoter via a novel and specific estrogen receptor (ER)-mediated mechanism. Our results show that treatment with epidermal growth factor or transfection of a constitutively active Ras mutant allows E₂ to induce the TGFß3 promoter via ER in cotransfected HeLa and osteosarcoma MG63 cells. Both protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors can block the combined stimulatory effect of E₂ and epidermal growth factor/Ras. However, E₂ induction of the TGFß3 promoter was found to be unaffected by mutation of ER serine 118, a well-characterized target of MAPK. Progressive deletion analysis of the ER amino-terminal region delineated three separate domains modulating the E₂/activated Ras response, revealing a complex functional organization of the ER A/B domain required for regulation of the TGFß3 promoter. In addition, PKC and MAPK inhibitors had no effect on the induction of TGFß3 promoter activity by the SERM EM-652. These results indicate that induction of the TGFß3 promoter by the E₂/ER complex requires the concomitant activation of PKC and MAPK signaling and provide a novel framework for the design of more effective estrogen-based therapeutic strategies.

This article has been cited by other articles:

				R. C. Y. Choi, Q. T. Gao, A. W. H. Cheung, J. T. T. Zhu, F. T. C. Lau, J. Li, W. Z. M. Li, G. K. Y. Chu, R. Duan, J. K. H. Cheung, et al. A Chinese Herbal Decoction, Danggui Buxue Tang, Stimulates Proliferation, Differentiation and Gene Expression of Cultured Osteosarcoma Cells: Genomic Approach to Reveal Specific Gene Activation Evid. Based Complement. Altern. Med., January 8, 2009; (2009) nen085v1. [Abstract] [Full Text] [PDF]

				K. Britt, A. Ashworth, and M. Smalley Pregnancy and the risk of breast cancer Endocr. Relat. Cancer, December 1, 2007; 14(4): 907 - 933. [Abstract] [Full Text] [PDF]

				R. H. Straub The Complex Role of Estrogens in Inflammation Endocr. Rev., August 1, 2007; 28(5): 521 - 574. [Abstract] [Full Text] [PDF]

				T Mankame, R Hokanson, R Fudge, R Chowdhary, and D Busbee Alteration of gene expression in human cells treated with the agricultural chemical diazinon: possible interaction in fetal development Human and Experimental Toxicology, May 1, 2006; 25(5): 225 - 233. [Abstract] [PDF]

				B. Chen, D. Zhang, and J. W. Pollard Progesterone Regulation of the Mammalian Ortholog of Methylcitrate Dehydratase (Immune Response Gene 1) in the Uterine Epithelium during Implantation through the Protein Kinase C Pathway Mol. Endocrinol., November 1, 2003; 17(11): 2340 - 2354. [Abstract] [Full Text] [PDF]

				K. L. Porter, S. Chanda, H. Q. Wang, K. W. Gaido, R. C. Smart, and C. L. Robinette 17{beta}-Estradiol Is a Hormonal Regulator of Mirex Tumor Promotion Sensitivity in Mice Toxicol. Sci., September 1, 2002; 69(1): 42 - 48. [Abstract] [Full Text] [PDF]

				K. W. Braun, M.-N. Vo, and K. H. Kim Positive Regulation of Retinoic Acid Receptor Alpha by Protein Kinase C and Mitogen-Activated Protein Kinase in Sertoli Cells Biol Reprod, July 1, 2002; 67(1): 29 - 37. [Abstract] [Full Text] [PDF]

				A. Matejuk, J. Dwyer, A. Zamora, A. A. Vandenbark, and H. Offner Evaluation of the Effects of 17{beta}-Estradiol (17{beta}-E2) on Gene Expression in Experimental Autoimmune Encephalomyelitis Using DNA Microarray Endocrinology, January 1, 2002; 143(1): 313 - 319. [Abstract] [Full Text] [PDF]